CN106822176B - The purposes of lithium chloride inhibition foot and mouth disease virus - Google Patents
The purposes of lithium chloride inhibition foot and mouth disease virus Download PDFInfo
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- CN106822176B CN106822176B CN201710146292.3A CN201710146292A CN106822176B CN 106822176 B CN106822176 B CN 106822176B CN 201710146292 A CN201710146292 A CN 201710146292A CN 106822176 B CN106822176 B CN 106822176B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
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Abstract
The present invention designs a kind of using lithium chloride as the foot and mouth disease virus inhibitor of effective component, belong to field of medicaments, wherein, the activity of lithium chloride is not higher than 40mmol/L, it is the most obvious to the inhibiting effect of foot and mouth disease virus in the concentration range of 20-40mmol/L, duplicate stage in mouth disease virus infection occurs for the inhibiting effect, and further, the early stage replicated in foot and mouth disease virus occurs for the inhibiting effect.In addition, lithium chloride is single at distinguishing one from the other, more significant to the effect of mouth disease virus infection, this is just the condition that lithium chloride is applied to the research of the molecule or cytology research and progress Antiviral Effect of foot and mouth disease virus and lays a good foundation and provides convenience.
Description
Technical field
The present invention relates to chemical substance field of medicaments purposes, more particularly to a kind of using lithium chloride as effective component
Foot and mouth disease virus inhibitor.
Background technique
Aftosa (Foot-and-mouth disease, FMD) is by foot and mouth disease virus (Foot-and-mouth
Disease virus, FMDV) caused by one kind is acute, hot, highly contagious disease, domestic animal and wild idol can be infected
Hoof animal, including ox, pig, sheep, camel and deer etc..Since in the world, All Countries have aftosa to be easy by accident or have
After the report of the transboundary propagation of meaning, its host range is extensively and fast propagation has caused the pass of International Animal Health tissue
Note.Huge economic losses and social influence, World Organization for Animal Health (World Organisation can be caused in view of FMD
For Animal Health, OIE) and FAO (Food and Agriculture Organization of the United Nation) (FAO) be listed in first of A class zoonosis, China
It is listed in first of a kind of zoonosis, sufficiently shows the degree of concern both at home and abroad to FMD.It is to endanger animal husbandry
" number one killer " to develop in a healthy way, and influence the most important disease of animal and animal's products international trade.Up to the present, I
State takes the comprehensive measures for the prevention and control based on vaccine immunity to achieve certain effect for aftosa.But due to aftosa epidemic disease
Seedling is a kind of inactivated vaccine, exists and induces immune time end, usually only four months or so, and be more toxic, cause
Allergic reaction make animal husbandry loss increase the disadvantages of.In addition, foot and mouth disease virus is a kind of virus with extensive variability,
Its antigenicity also usually morphs therewith.More some researches show that a regional drove is infused by effective aftosa vaccine
, again can be popular again within the 1-2 month after penetrating, this is because caused by the virus morphs.Therefore, there is an urgent need to research and develop one kind
Can effectively foot-and-mouth disease virus resistant drug, inhibit or control the infection of FMDV by aggregate measures.
LiCl is a kind of common spiritual stability agent, and being used to treat abalienation and depression in physianthropy has had closely
60 years history.Other than the effect set the mind at rest, LiCl is also found to for treating some neurological disorders diseases for example
Alzheimer disease syndrome.Lithium salts is also reported, and to tumour cell, there are inhibiting effect.But LiCl whether there is shadow to FMDV
It rings, influencing mechanism is as how there has been no reports.
Summary of the invention
The problem of preventing and treating process for current FMDV, the present invention intend providing a kind of using lithium chloride as effective component
Foot and mouth disease virus inhibitor.The inhibitor can effectively inhibit the duplication of FMDV in vitro, guarantee normal cell activity rate
Under the premise of, the virus titer of foot and mouth disease virus can be reduced to about 67%, mRNA expression decline about 90%.
The present invention provides a kind of foot and mouth disease virus inhibitor, and the effective component of the inhibitor is lithium chloride；Lithium chloride
Activity is not higher than 40mmol/L.
Further, the activity of the lithium chloride is 20-40mmol/L.
Further, lithium chloride the inhibition of foot and mouth disease virus occurs the duplicate stage in virus infection.
Further, the inhibition of foot and mouth disease virus occurs early stage duplicate stage for lithium chloride.
Further, lithium chloride inhibits duplication of the foot and mouth disease virus in BHK-21 cell.
Beneficial effects of the present invention:
1, foot and mouth disease virus inhibitor of the present invention carries out the inhibition of mouth disease virus infection based on lithium chloride,
The inhibitor can occur from the external effective duplication for inhibiting FMDV and translation process, the inhibiting effect in foot and mouth disease virus
The duplicate stage of infection, further, in early stage duplicate stage, more precisely, mainly in the preceding 12h of duplicate stage, multiple
In the rear 12h in stage processed, lithium chloride does not influence virus.During Foot-and-mouth disease virus Infectious Cycle, lithium chloride is to disease
It the absorption of poison and penetrates ability and has little effect, in addition, lithium chloride is single at distinguishing one from the other, this is just that lithium chloride is applied to mouth
The item that the molecule or cytology research of aphtovirus and the research for carrying out Antiviral Effect lay a good foundation and provides convenience
Part.
2, foot and mouth disease virus inhibitor of the present invention is able to suppress the duplication of foot and mouth disease virus based on lithium chloride, proposes
It is preparing the application in foot-and-mouth disease virus resistant drug, when chlorination lithium concentration is not higher than 40mmol/L, can guarantee normal thin
Cytoactive rate is 90% or more, while when chlorination lithium concentration is 40mmol/L, compared to negative control group, the disease of foot and mouth disease virus
Malicious titre reduces about 67%, and viral mRNA expression decline about 90% has significant antivirus action, is prepared into resisting
Hoof-and-mouth disease cytotoxic drug prepares that simple, easy to use, cost is relatively low, the action period is longer compared to common vaccine immunity.
In addition, lithium chloride to the inhibiting effect of foot and mouth disease virus occur mainly in virus duplicate stage, especially in the 0-12h of early stage most
To be significant, this is just to have established theoretical basis using lithium chloride related drugs to prevent and treat mouth disease virus infection.
Detailed description of the invention
Fig. 1 is toxicity data figure of the LiCl to BHK-21 cell of various concentration；
Fig. 2 is influence disparity map of the LiCl of various concentration to FMDV virus titer；
Fig. 3 is influence disparity map of the LiCl to viral mRNA expression of various concentration；
Fig. 4 is influence disparity map of the LiCl of viruses adsorption stage various concentration to FMDV virus titer；
Fig. 5 is influence disparity map of the LiCl to viral mRNA expression of viruses adsorption stage various concentration；
Fig. 6 is that virus penetrates influence disparity map of the LiCl of stage various concentration to FMDV virus titer；
Fig. 7 is influence disparity map of the LiCl to viral mRNA expression that virus penetrates stage various concentration；
Fig. 8 is influence disparity map of the LiCl of virus replication phase various concentration to FMDV virus titer；
Fig. 9 is influence disparity map of the LiCl to viral mRNA expression of virus replication phase various concentration；
Figure 10 is influence disparity map of the different time sections dosing to FMDV virus titer in virus replication；
Figure 11 is the different time sections dosing in virus replication to the influence disparity map of viral mRNA expression.
Specific embodiment
The present invention passes through specific test example the present invention will be further explained explanation.
Solution is prepared: chlorination lithium powder, which is dissolved in DMEM cell culture fluid, makes its final concentration of 1 mol/L, then passes through
0.22 μm of sterilizing filter filtration sterilization is configured to lithium chloride stoste, spare.
The cytotoxicity of 1 LiCl of test example detects
In order to detect influence of the LiCl for normal cell growth, using Cell Counting Kit-8(CCK8) reagent
Box detects the cytotoxicity of LiCl.Specific steps are as follows: will be well-grown on DMEM cell culture fluid
BHK-21 cell reaches 96 porocyte plates, after cell covers with single layer, discards cell culture fluid, washes 3 times with PBS solution, then
100 μ L series of concentrations are added and (LiCl are diluted to 10,20,30,40,60,80 and 100 respectively with serum-free cell culture medium
The medicine of various concentration is set up three repetitions, while setting up negative control (being added without drug) and blank pair by drug mmol/L)
According to (culture solution is only added without cell), it is put into 37 DEG C of incubators and cultivates 48h.100 μ L are added into every hole after PBS rinse to contain
10% CCK8 solution continues in 37 DEG C of incubators to cultivate 1-4h, measures absorbance value of every hole at 450nm with microplate reader.Using
Following formula calculates various concentration drug to the toxicity of cell: cell activity rate (%)=[(ODDrug-ODBlank)/(ODIt is negative-ODBlank)]*
100.So that 50% cell generates the drug concentration (CC of cytopathy50) calculated by GraphPad Prism software.
As shown in Figure 1, being continuously increased with chlorination lithium concentration increases the toxicity of normal cell.When lithium chloride is dense
When degree is not higher than 40mmol/L, cell activity rate is 90% or more；When chlorination lithium concentration is higher than 40mmol/L, cell activity is fast
Speed decline, under the chlorination lithium concentration of 100mmol/L, cell activity rate only has 30%.So when preparing anti-mouth using lithium chloride
When aphtovirus drug, concentration should be not higher than 40mmol/L.
Determination of 2 LiCl of test example to the antiviral activity of foot and mouth disease virus
It has been determined that LiCl verifies the antiviral activity of foot and mouth disease virus by following experiment by following agreement.Tool
Steps are as follows for gymnastics work: 24 porocyte plates will be reached by well-grown BHK-21 cell on DMEM cell culture fluid, to cell
After covering with single layer, cell culture fluid is discarded, is washed 3 times with PBS solution, every hole is inoculated with FMDV(MOI=0.1) while being added serial dense
The LiCl(of degree is respectively 10,20,30,40 mmol/L), three repetitions are set up, while setting non-dosing object but being inoculated with pair of FMDV
According to.48h is cultivated in 37 DEG C of incubators.Virus liquid is discarded, is washed with the PBS of pre-cooling three times to remove free virus, every hole is added
400 μ L culture solutions, are put into -20 DEG C of refrigerator multigelations 3 times, collect virus liquid, it is broken that 10000rpm is centrifuged 10min removal cell
Piece, measurement and detection mRNA expression situation of the supernatant for virus titer.
As shown in Figure 2, be separately added into 0,10,20,30, the lithium chloride of 40mmol/L concentration in the case where, the disease of FMDV
Malicious titre declines in gradient, illustrates in certain concentration range, and lithium chloride is capable of the duplication of gradient inhibition foot and mouth disease virus, into
One step is from the figure 3, it may be seen that lithium chloride is capable of the expression of gradient inhibition foot and mouth disease virus mRNA.In addition, dense in 20-40mmol/L
It spends in range, lithium chloride inhibits significant to the virus titer and mRNA expression of foot and mouth disease virus.
The detection in 3 FMDV suppressing virus replication stage of test example
1. the viruses adsorption stage
Whether have an impact to viruses adsorption BHK-21 cell for inspection LiCl, BHK-21 cell is reached in 24 orifice plates, to
After cell covers with single layer, culture solution is discarded, every hole is added the FMDV virus liquid (MOI=0.1) of 200 μ L, is then added into every hole
The 200 μ L of LiCl of various concentration, making the final concentration of LiCl is respectively 10,20,30 and 40mmol/L, sets up and is added without drug
Cell plates are put into 4 DEG C of refrigerator effect 1h, only virus are allowed to be attached to cell surface by negative control.Virus liquid is discarded, PBS is used
Free virus is washed away, every hole is added 400 μ L culture solutions, is put into -20 DEG C of refrigerator multigelations 3 times, virus liquid is collected,
10000rpm is centrifuged 10min and removes cell fragment, measurement and detection mRNA expression situation of the supernatant for virus titer.
By Fig. 4 and Fig. 5 it is found that in the viruses adsorption stage, carried out respectively with the lithium chloride of various concentration and FMDV virus liquid
BHK-21 cell is handled, in 4 DEG C of refrigerator collective effect 1h.The either LiCl of which kind of concentration handles cell, virus as the result is shown
Titre and mRNA expression and untreated fish group and no significant difference, so LiCl can't adsorb BHK-21 cell to FMDV
It has an impact.
2. virus penetrates the stage
Whether have an impact to the BHK-21 cell that penetrates of virus for inspection LiCl, BHK-21 cell reached in 24 orifice plates,
After cell covers with single layer, culture solution is discarded, every hole is added the FMDV virus liquid (MOI=0.1) of 200 μ L, cell plates are put into 4
DEG C refrigerator 1h allows virus absorption onto cell surface, after the unbonded virus of PBS liquid removal, is then added into every hole different
The 200 μ L of LiCl of concentration, making the final concentration of LiCl is respectively 10,20,30 and 40mmol/L, while setting up the yin that drug is not added
Property control, cell plates are put into 37 DEG C of incubator culture 1h, discard drug, wash away remaining drug with PBS, addition contains 2%FBS
Maintaining liquid, be put into 37 DEG C of incubators continue cultivate 48h, collect supernatant carry out virus titer measurement and detection mRNA expression
Situation.
Virus function cells 1h under the conditions of 4 DEG C, guarantees that virus has been adsorbed on cell surface, is added later different dense
The LiCl of degree and in 37 DEG C of incubation 1h, virus occurs to enter process under this condition, removes LiCl later, supplements new culture solution and go
The LiCl of influence except to(for) the stage after cell entry, by Fig. 6 and Fig. 7 it is found that the virus titer and mRNA table of each drug-treated group
Up to level compared with the negative control without drug-treated group (0mmol/L) no marked difference, illustrate that virus will not be by LiCl
It influences, the ability into cell does not change.
3. virus replication phase
Whether inhibiting effect is replicated on BHK-21 cell to FMDV for analysis LiCl, BHK-21 cell is reached into 24 holes
In plate, after cell covers with single layer, culture solution is discarded, every hole is added the FMDV virus liquid (MOI=0.1) of 200 μ L, is placed in 37 DEG C
Incubator culture 1h guarantees that virus completes absorption and penetrates process, discards virus liquid, various concentration is then added into every hole
200 μ L of LiCl, making the final concentration of LiCl is respectively 10,20,30 and 40mmol/L, while setting up the negative control that drug is not added,
37 DEG C of incubators are put into continue to cultivate 48h.The infection conditions of virus pass through virus titer respectively and detection mRNA expression carries out
Measurement.
By Fig. 8 and Fig. 9 it is found that virus function cells 1h under the conditions of 37 DEG C, is then added the drug of various concentration, herein
Under the conditions of, virus has been completed absorption and enters the stage, and drug also can only act on the duplicate stage of virus.Shown in Fig. 8,
Virus titer with concentration raising downward trend in gradient, especially under 20,30,40mmol/L chlorination lithium concentration, virus titer
Downward trend is extremely significant, illustrates that LiCl is able to suppress duplication of the FMDV on BHK-21 cell；As shown in Figure 9, mRNA expresses water
The flat raising downward trend in gradient with concentration, in the case where chlorination lithium concentration is 10mmol/L, the horizontal downward trend of rna expression is extremely aobvious
It writes, illustrates that LiCl is able to suppress the synthesis of mRNA in FMDV reproduction process, the i.e. translation process of FMDV.
The detection of 4 FMDV suppressing virus replication phases-time section of test example
It is inhibited in order to analyze which that LiCl replicates FMDV on BHK-21 cell in period, use timesharing
Between the mode of section dosing studied.BHK-21 cell is reached in 24 orifice plates, after cell covers with single layer, discards culture solution,
The FMDV virus liquid (MOI=0.1) that 200 μ L are added in every hole is added, is placed in 37 DEG C of incubator culture 1h, guarantee virus complete absorption and
Process is penetrated, virus liquid is discarded, the cell culture fluid of 2%FBS is added, is denoted as 0h at this time, in time interval 0-2,2-4,4-6,6-
8, LiCl is added into different holes respectively in 8-10,10-12,12-14,14-16,16-18,18-24h, reaches the final concentration of drug
To 40mmol/L, while the negative control that drug is not added is set up, 37 DEG C of incubator cultures collect different groups of supernatants to after for 24 hours, into
The measurement of row virus titer and detection mRNA expression situation.
The inhibition feelings of the different times of FMDV duplication are analyzed by detection supernatant virus titer and mRNA expression
Condition, as a result as shown in Figure 10 and Figure 11, in the 0-10h of FMDV duplication, compared with negative control, virus titer downward trend pole
Significantly, downward trend is significant in 10-12h, and 12-24h inner virus titre downward trend is not obvious；Further, multiple in FMDV
In the 0-10h of system, compared with negative control, viral mRNA expression downward trend is extremely significant, downward trend in 10-12h
Significantly, the mRNA expression downward trend of 12-24h inner virus is not obvious.Illustrate LiCl only early stage FMDV duplication
The later period LiCl for working, and entering virus replication cannot prevent the duplication of virus.
By the Cell-based assays of above-described embodiment 1- 4 it is found that the lithium chloride of 10-40mmol/L concentration can significantly press down
Make the expression of virus mRNA, the further virus titer for inhibiting virus, in the premise for not influencing normal cell activity rate
Under, inhibitory effect is significant, and compared to negative control, viral mRNA expression decline about 90%, viral virus titer is reduced
About 67%.In addition, being analyzed respectively by the different phase to virus infected cell it is found that the inhibition of virus occurs mainly in
Duplicate stage further studies the different time sections of duplicate stage, and discovery lithium chloride is main to the inhibiting effect of virus
Occur in early stage duplicate stage, wherein foot and mouth disease virus is pressed down with significantly, studying above-mentioned lithium chloride in the 0-12h of early stage
The reaction mechanism of system, for lithium chloride to be applied to the molecular biology research of foot and mouth disease virus and researches and develops anti-mouth hoof using lithium chloride
The drug of epidemic disease poison develops application of the lithium chloride in terms of preparing foot-and-mouth disease virus resistant drug and provides theoretical premise and condition.
Wherein, the otherness of above-mentioned each experimental group and drug untreated fish group (0 mmol/L group) utilizes GraphPad
Prism5 software carries out variable analysis (ANOVA).Data are shown according to ± standard deviation (SD).It is anticipated using t check analysis statistics
Justice.
Embodiment of the present invention be it is illustrative, do not limited the scope of the invention with this, but with essence of the invention
Based on mind, any further extension or improvement, all belong to the scope of protection of the present invention.
Claims (4)
1. lithium chloride inhibits the purposes in hoof-and-mouth disease cytotoxic drug in preparation, wherein concentration of the lithium chloride in the drug is
20-40 mmol/L。
2. purposes as described in claim 1, it is characterised in that: the inhibition of foot and mouth disease virus occurs in virus infection for lithium chloride
Duplicate stage.
3. purposes as claimed in claim 2, it is characterised in that: the inhibition of foot and mouth disease virus occurs in duplicate stage for lithium chloride
Early stage.
4. purposes as claimed in claim 2, it is characterised in that: lithium chloride inhibits foot and mouth disease virus answering in BHK-21 cell
System.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103893206A (en) * | 2014-04-24 | 2014-07-02 | 中国药科大学 | Application of lithium chloride used as Hedgehog signal path inhibitor for preparing anti-pancreatic cancer medicines |
| WO2016097031A1 (en) * | 2014-12-18 | 2016-06-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Gsk3b and uses thereof in the diagnostic and treatment of hypopigmentation disorders |
| WO2016207366A1 (en) * | 2015-06-26 | 2016-12-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of viral infections |
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2017
- 2017-03-13 CN CN201710146292.3A patent/CN106822176B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103893206A (en) * | 2014-04-24 | 2014-07-02 | 中国药科大学 | Application of lithium chloride used as Hedgehog signal path inhibitor for preparing anti-pancreatic cancer medicines |
| WO2016097031A1 (en) * | 2014-12-18 | 2016-06-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Gsk3b and uses thereof in the diagnostic and treatment of hypopigmentation disorders |
| WO2016207366A1 (en) * | 2015-06-26 | 2016-12-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of viral infections |
Non-Patent Citations (2)
| Title |
|---|
| 《Antiviral effect of lithium chloride on infection of cells by porcine parvovirus》;Ye Chen et al.;《ARCHIVES OF VIROLOGY》;20150430;第160卷(第4期);第1015-1020页 * |
| 氯化锂对新城疫病毒在鸡胚成纤维细胞内复制的影响;傅安静 等;《黑龙江畜牧兽医》;20150610(第2015-06期);第219-221页 * |
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